Scutellarein attenuates atopic dermatitis by selectively inhibiting transient receptor potential vanilloid 3 channels

Abstract

Background and Purpose Atopic dermatitis (AD) is one of the most common chronic inflammatory cutaneous diseases with unmet clinical needs. As a common ingredient found in several medicinal herbs with efficacy on cutaneous inflammatory diseases, Scutellarein (Scu) has been shown to possess anti‐inflammatory and anti‐proliferative activities. We aimed to evaluate the therapeutic efficacy of Scu against AD and its underlying molecular mechanism. Experimental Approach Efficacy of Scu on AD was evaluated in 2,4‐dinitrofluorobenzene (DNFB) and carvacrol‐induced dermatitis mouse models. Cytokine mRNA and serum IgE levels were examined using qPCR and ELISA, respectively. Voltage clamp recordings were used to measure currents mediated by transient receptor potential (TRP) channels. In silico docking, site‐direct mutagenesis, and covalent modification were used to explore the binding pocket of Scu on TRPV3. Key Results Subcutaneous administration of Scu efficaciously suppresses DNFB and carvacrol‐induced pruritus, epidermal hyperplasia and skin inflammation in wild type mice but has no additional benefit in Trpv3 knockout mice in the carvacrol model. Scu is a potent and selective TRPV3 channel allosteric negative modulator with an apparent affinity of 1.18 μM. Molecular docking coupled with site‐direct mutagenesis and covalent modification of incorporated cysteine residues demonstrate that Scu targets the cavity formed between the pore helix and transmembrane helix S6. Moreover, Scu attenuates endogenous TRPV3 activity in human keratinocytes and inhibits carvacrol‐induced proliferative and proinflammatory responses. Conclusion and Implications Collectively, these data demonstrate that Scu ameliorates carvacrol‐induced skin inflammation by directly inhibiting TRPV3, and TRPV3 represents a viable therapeutic target for AD treatment.

Selective inhibition of overactive warmth-sensitive Ca2+-permeable TRPV3 channels by antispasmodic agent flopropione for alleviation of skin inflammation

“…It has been shown that the suppression of overactive TRPV3 channel function through gene silencing or the use of channel inhibitors reduces skin lesions ( 30 , 31 ). We, therefore, generated a mouse model of dorsal skin inflammation induced by topical applications of skin sensitizer DNFB at a concentration of 0.5% once a day on the first day and subsequent 0.2% DNFB once a day for 2 days ( Fig.…”

Autophagy Induction by Scutellaria Flavones in Cancer: Recent Advances

“…Moreover, it is functionally related to apigenin [ 41 ]. Recent research has focused on scutellarein owing to its interesting bioprotective properties, including anticancer, antiproliferative and antioxidant activities [ 42 ] ( Table 1 ). Interestingly, being a flavone, its structure is based upon the backbone of -phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) [ 43 ].…”

“…Therefore, this approach helps determine the concentrations and forms of such compounds in plasma and tissue. In addition, most flavonoids tend to bind sugars as b-glycosides, which further determine their absorption directly from the small intestine or through the colon [ 42 ]. Interestingly, before absorption, the dietary flavonoids must be released by chewing or digestion via digestive juices (gastrointestinal tract) followed by the action of microorganisms in the colon.…”

Temperature Sensitive Contact Modes Allosterically Gate TRPV3

“…For instance, T636's contact with Y594 is the primary edge between the Pore and S5 helices and is directly adjacent to the S6 pi bulge [51]. Mutating T636 to serine resulted in a hyperactive mutant [52] and this same position is known to be a binding site for the inhibitor scutellarin [53]. A highly central inter-protomer edge passes through M572 and F592, between the PC6 cluster and region associated with Olmsted Syndrome.…”